Substance P is probably the transmitter used at synapses made by primary sensory neurons (their cell bodies are in the dorsal root ganglia) with spinal interneurons in the dorsal horn of the spinal column, and thus it is an example of a peptide acting as a primary transmitter at a synapse.
Enkephalins act to decrease the release of substance P at these synapses and thereby inhibit the pathway for pain sensation at the first synapse in the pathway.
This is the newest category of neurotransmitter to be defined and stretches the usual definition of synaptic transmission even further than neuropeptides do. Gas neurotransmitters are neither packaged into synaptic vesicles nor released by exocytosis. Instead, gas neurotransmitters are highly permeant and simply diffuse from synaptic terminals to neighboring cells after synthesis, their synthesis being triggered by depolarization of the nerve terminal (the influx of Ca++ activates synthetic enzymes). Moreover, there are no specific reuptake mechanisms, nor do they undergo enzymatic destruction, so their action appears to be ended by diffusion or binding to superoxide anions or various scavenger proteins. Both nitric oxide (NO) and carbon monoxide (CO) are examples of gaseous neurotransmitters. NO is a transmitter at synapses between inhibitory motor neurons of the enteric nervous system and gastrointestinal smooth muscle cells (see ). NO also functions as a neurotransmitter in the CNS. The enzyme NO synthase catalyzes the production of NO as a product of the oxidation of arginine to citrulline. This enzyme is stimulated by an increase in cytosolic [Ca++].
In addition to serving as a neurotransmitter, NO functions as a cellular signal transduction molecule both in neurons and in nonneuronal cells (e.g., vascular smooth muscle; see
Chapter 14).
One way that NO functions as a signal transduction molecule is by regulating guanylyl cyclase, the enzyme that produces cGMP from GTP. NO binds to a heme group in soluble guanylyl cyclase and potently stimulates the enzyme. Stimulation of this enzyme leads to an elevation in cGMP in the target cell. The cGMP can then influence multiple cellular processes.
The multitude of neurotransmitters used in the nervous system provides it with a specific and flexible interneuronal communications system. These characteristics are even further enhanced by the variety of receptors for each neurotransmitter. Receptors for a particular neurotransmitter were traditionally distinguished primarily by pharmacological differences in their sensitivity to particular agonists and antagonists. For example, acetylcholine receptors were split into muscarinic and nicotinic classes, depending on whether they bind muscarine or nicotine. Similarly, glutamate receptors were split into three main groups according to their sensitivity to the agonists NMDA, kainic acid, or AMPA. Though useful, this classification scheme has several limitations: some receptors fail to be activated by agonists, and it fails to disclose all the various receptor subtypes for a particular transmitter. Over the past 15 years or so, molecular biological approaches have been used to identify and sequence the receptor genes for many of the known neurotransmitters. It is thought that we now have a relatively complete catalog of the genes for these receptors. What this work has revealed is that there is a tremendous diversity of actual and potential receptor subtypes that are or could be used by the nervous system. Moreover, knowledge of the gene sequences has enabled an understanding of the relationship of different receptor proteins to each other and to other important proteins. This knowledge, combined with the results of biochemical, crystallographic, and other types of studies, has led to a much deeper understanding of the structural and functional workings of receptor proteins. In particular, various receptors can be grouped into families based on gene sequences, and members of each family share various structural and functional features.